Classifications

• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/33—Heterocyclic compounds
  • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
  • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
  • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/33—Heterocyclic compounds
  • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
  • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
  • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
  • A61K31/445—Non condensed piperidines, e.g. piperocaine
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/33—Heterocyclic compounds
  • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
  • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/33—Heterocyclic compounds
  • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
  • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
  • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
  • A61K31/445—Non condensed piperidines, e.g. piperocaine
  • A61K31/452—Piperidinium derivatives
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
  • A61P31/12—Antivirals
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
  • A61P31/12—Antivirals
  • A61P31/20—Antivirals for DNA viruses
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
  • C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
  • C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
  • C07D211/36—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
  • C07D211/40—Oxygen atoms
  • C07D211/44—Oxygen atoms attached in position 4
  • C07D211/46—Oxygen atoms attached in position 4 having a hydrogen atom as the second substituent in position 4
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
  • C07D307/02—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings
  • C07D307/34—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
  • C07D307/38—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with substituted hydrocarbon radicals attached to ring carbon atoms
  • C07D307/40—Radicals substituted by oxygen atoms
  • C07D307/46—Doubly bound oxygen atoms, or two oxygen atoms singly bound to the same carbon atom
  • C07D307/48—Furfural

Definitions

• the present application relates to iminosugars and methods of treating viral infections with iminosugars and, in particular, to the use of iminosugars for treatment and/or prevention of viral infections caused by or associated with a virus belonging to the Poxviridae family.
• One embodiment is a method of treating or preventing a disease or condition caused by or associated with a virus belonging to the Poxviridae family, which method comprises administering to a subject in need thereof an effective amount of a compound of the formula,
• R is either selected from substituted or unsubstituted alkyl groups, substituted or unsubstituted cycloalkyl groups, substituted or unsubstituted aryl groups, or substituted or unsubstituted oxaalkyl groups; or wherein R is
• Ri is a substituted or unsubstituted alkyl group
• Xi-5 are independently selected from H, N0 2 , N 3 , or NH 2 ;
• Y is absent or is a substituted or unsubstituted Ci-alkyl group, other than carbonyl; and Z is selected from a bond or NH; provided that when Z is a bond, Y is absent, and provided that when Z is NH, Y is a substituted or unsubstituted Ci-alkyl group, other than carbonyl; and
• W 1-4 are independently selected from hydrogen, substituted or unsubstituted alkyl groups, substituted or unsubstituted haloalkyl groups, substituted or unsubstituted alkanoyl groups, substituted or unsubstituted aroyl groups, or substituted or unsubstituted haloalkanoyl groups.
• Another embodiment is a method of infectivity of a cell infected with a virus belonging to the Poxviridae family, which method comprises contacting a cell infected with a virus belonging to the Poxviridae family with an effective amount of a compound of the formula,
• R is either selected from substituted or unsubstituted alkyl groups, substituted or unsubstituted cycloalkyl groups, substituted or unsubstituted aryl groups, or substituted or unsubstituted oxaalkyl groups; or wherein R is
• Ri is a substituted or unsubstituted alkyl group
• X 1-5 are independently selected from H, N0 2 , N 3 , or NH 2 ;
• Y is absent or is a substituted or unsubstituted Q -alkyl group, other than carbonyl; and Z is selected from a bond or NH; provided that when Z is a bond, Y is absent, and provided that when Z is NH, Y is a substituted or unsubstituted Ci-alkyl group, other than carbonyl; and
• W 1-4 are independently selected from hydrogen, substituted or unsubstituted alkyl groups, substituted or unsubstituted haloalkyl groups, substituted or unsubstituted alkanoyl groups, substituted or unsubstituted aroyl groups, or substituted or unsubstituted haloalkanoyl groups.
• Figures 1(A)-(E) present chemical formulas of the following iminosugars: A) N-Butyl deoxynojirimycin (NB-DNJ, UV-1); B) N-Nonyl deoxynojirimycin (NN-DNJ, UV-2); C) N- (7-Oxadecyl)deoxynojirimycin (N7-0-DNJ, UV-3); D) N-(9-Methoxynonyl)
• UV-4 deoxynojirimycin
• E N-(N- ⁇ 4'-azido-2'-nitrophenyl ⁇ -6- aminohexyl)deoxynoj irimycin (UV-5) .
• Figure 2 is a synthesis scheme for NN-DNJ.
• Figures 3A-D illustrate synthesis of N7-0-DNJ.
• Figure 3A shows a sequence of reactions leading to N7-0-DNJ
• Figure 3B illustrates preparation of 6-propyloxy-l- hexanol
• Figure 3C illustrates preparation of 6-propyloxy-l-hexanal
• Figure 3D illustrates synthesis of N7-0-DNJ.
• Figures 4A-C relate to synthesis of N-(9-Methoxynonyl) deoxynojirimycin.
• Figure 4A illustrates preparation of 9-methoxy-l-nonanol
• Figure 4B illustrates preparation of 9-methoxy-l-nonanal
• Figure 4C illustrates synthesis of N-(9-Methoxynonyl)
• Figure 5 presents in vivo survival data for mice infected with cowpox virus.
• Figure 6 presents in vivo safety data for UV-4 and UV-5.
• viral infection describes a diseased state, in which a virus invades a healthy cell, uses the cell's reproductive machinery to multiply or replicate and ultimately lyse the cell resulting in cell death, release of viral particles and the infection of other cells by the newly produced progeny viruses. Latent infection by certain viruses is also a possible result of viral infection.
• the term "treating or preventing viral infection” means to inhibit the replication of the particular virus, to inhibit viral transmission, or to prevent the virus from establishing itself in its host, and to ameliorate or alleviate the symptoms of the disease caused by the viral infection.
• the treatment is considered therapeutic if there is a reduction in viral load, decrease in mortality and/or morbidity.
• IC50 or IC90 is a concentration of a therapeutic agent, such as an iminosugar, used to achieve 50% or 90% reduction of viral load, respectively. Disclosure
• such iminosugars may be useful for treating or preventing a disease or condition caused by or associated with a virus belonging to the Poxviridae family.
• the Poxviridae family includes the Chordopoxviridae subfamily and the Entomopoxviridae subfamily.
• the Chordopoxviridae subfamily includes Orthopox genus, Parapox genus;
• Aviropox genus Capripoxvirus genus; Leporipoxvirus genus; Suipoxvirus genus;
• the Entomopoxviridae subfamily includes
• Entomopoxviruses A, B and C may infect humans.
• Viruses belonging to the Orthopoxvirus genus of the Poxviridae family include Buffalopox virus; Camelpox virus; Cowpox virus; Ectromelia virus; Monkeypox virus; Rabbitpox virus; Raccoonpox virus; Sealpox virus; Skunkpox virus; Taterapox virus; Uasin Gishu disease virus; Vaccinia virus; Variola virus; and Volepox virus.
• orthopoxviruses Diseases caused by or associated with orthopoxviruses include Buffalopox; Camelpox;
• Cowpox Cowpox; Mousepox (cause by Ectromelia virus); Monkeypox; Rabbitpox, also known as Green Rabbit Syndrome; Raccoonpox; Sealpox; Skunkpox; Taterapox; Uasin Gishu disease; Smallpox; and Volepox.
• Viruses belonging to the Parapox genus of the Poxviridae family include orf virus, pseudocowpox and bovine papular stomatitis virus.
• parapoxviruses Diseases caused by or associated with parapoxviruses include orf, pseudocowpox and bovine papular stomatitis.
• Viruses belonging to the Yatapox genus of the Poxviridae family include tanapox virus and yaba monkey tumor virus.
• Molluscum contagiosum virus is an example of a molluscipox virus, i.e. a virus belonging to the Molluscipox genus of the Poxviridae family.
• the iminosugar may be N-substituted deoxynojirimycin.
• as the N-substituted deoxynojirimycin may be a compound of the following formula:
• W 1-4 are independently selected from hydrogen, substituted or unsubstituted alkyl groups, substituted or unsubstituted haloalkyl groups, substituted or unsubstituted alkanoyl groups, substituted or unsubstituted aroyl groups, or substituted or unsubstituted haloalkanoyl groups.
• R may be selected from substituted or unsubstituted alkyl groups, substituted or unsubstituted cycloalkyl groups, substituted or unsubstituted aryl groups, or substituted or unsubstituted oxaalkyl groups.
• R may be substituted or unsubstituted alkyl groups and/or substituted or unsubstituted oxaalkyl groups comprise from 1 to 16 carbon atoms, from 4 to 12 carbon atoms or from 8 to 10 carbon atoms.
• oxaalkyl refers to an alkyl derivative, which may contain from 1 to 5 or from 1 to 3 or from 1 to 2 oxygen atoms.
• oxaalkyl includes hydroxyterminated and methoxyterminated alkyl derivatives.
• R may be selected from, but is not limited to -(CH 2 )60CH3,
• R may be branched or unbranched, substituted or unsubstituted alkyl group.
• the alkyl group may be a long chain alkyl group, which may be C6-C20 alkyl group; C8-C16 alkyl group; or C8-C10 alkyl group.
• R may be a long chain oxaalkyl group, i.e. a long chain alkyl group, which may contain from 1 to 5 or from 1 to 3 or from 1 to 2 oxygen atoms.
• R may have the following formula
• Ri is a substituted or unsubstituted alkyl group
• X 1-5 are independently selected from H, N0 2 , N 3 , or NH 2 ;
• Y is absent or is a substituted or unsubstituted Ci-alkyl group, other than carbonyl; and Z is selected from a bond or NH; provided that when Z is a bond, Y is absent, and provided that when Z is NH, Y is a substituted or unsubstituted Ci-alkyl group, other than carbonyl.
• Z is NH and Ri-Y is a substituted or unsubstituted alkyl group, such as C2-C20 alkyl group or C4-C12 alkyl group or C4-C10 alkyl group.
• Xi is N0 2 and X 3 is N 3 . In some embodiments, each of X 2 , X 4 and X 5 is hydrogen.
• the iminosugar may be a DNJ derivative disclosed in U.S. Patent application publication no. 2007/0275998, which is incorporated herein by reference.
• the iminosugar may be one of the compounds presented in Figure 1.
• Methods of synthesizing deoxynojirimycin derivatives are disclosed, for example, in U.S. Patent Nos. 5,622,972, 5,200,523, 5,043,273, 4,994,572, 4,246,345, 4,266,025, 4,405,714, and 4,806,650 and U.S. Patent application publication no. 2007/0275998, which are all incorporated herein by reference.
• the iminosugar may be in a form of a salt derived from an inorganic or organic acid.
• Pharmaceutically acceptable salts and methods for preparing salt forms are disclosed, for example, in Berge et al. (J. Pharm. Sci. 66: 1-18, 1977). Examples of appropriate salts include but are not limited to the following salts: acetate, adipate, alginate, citrate, aspartate, benzoate, benzenesulfonate, bisulfate, butyrate, camphorate,
• camphorsulfonate digluconate, cyclopentanepropionate, dodecylsulfate, ethanesulfonate, glucoheptanoate, glycerophosphate, hemisulfate, heptanoate, hexanoate, fumarate, hydrochloride, hydrobromide, hydroiodide, 2-hydroxyethanesulfonate, lactate, maleate, methanesulfonate, nicotinate, 2-naphthalenesulfonate, oxalate, palmoate, pectinate, persulfate, 3-phenylpropionate, picrate, pivalate, propionate, succinate, tartrate, thiocyanate, tosylate, mesylate, and undecanoate.
• the iminosugar may also used in a form of a prodrug.
• Prodrugs of DNJ derivatives such as the 6-phosphorylated DNJ derivatives, are disclosed in U.S. Patents nos. 5,043,273 and 5,103,008.
• the iminosugar may be used as a part of a composition, which further comprises a pharmaceutically acceptable carrier and/ or a component useful for delivering the composition to an animal.
• a pharmaceutically acceptable carrier useful for delivering the compositions to a human and components useful for delivering the
• compositions to other animals such as cattle are known in the art. Addition of such carriers and components to the composition of the invention is well within the level of ordinary skill in the art.
• the pharmaceutical composition may consist essentially of N- substituted deoxynojirimycin, which may mean that the N-substituted deoxynojirimycin is the only active ingredient in the composition.
• N-substituted deoxynojirimycin may be administered with one or more additional antiviral compounds.
• the iminosugar may be used in a liposome composition, such as those disclosed in US publications nos. 2008/0138351 and 2009/0252785 as well as in US application No. 12/732630 filed March 26, 2010.
• the iminosugar such as a DNJ derivative, may be administered to a cell or an animal affected by a virus.
• the iminosugar may inhibit morphogenesis of the virus, or it may treat the individual.
• the treatment may reduce, abate, or diminish the virus infection in the animal.
• Animals that may be infected with poxviruses include mammals including bovids, such as buffalos, sheep, goats and cattle (cows); camels; rodents, such as mice, voles, and gerbils; leporids, such as rabbits and hares; raccoons; seals; skunks; equines, including horses;
• primates including monkeys and humans.
• the amount of iminosugar administered to an animal or to an animal cell to the methods of the invention may be an amount effective to inhibit the morphogenesis of a poxvirus from the cell.
• the term “inhibit” as used herein may refer to the detectable reduction and/or elimination of a biological activity exhibited in the absence of the iminosugar.
• the term “effective amount” may refer to that amount of the iminosugar necessary to achieve the indicated effect.
• treatment as used herein may refer to reducing or alleviating symptoms in a subject, preventing symptoms from worsening or progressing, inhibition or elimination of the causative agent, or prevention of the infection or disorder related to the poxvirus in a subject who is free therefrom.
• treatment of the disease caused by or associated with a virus may include destruction of the infecting agent, inhibition of or interference with its growth or maturation, and neutralization of its pathological effects.
• the amount of the iminosugar which may be administered to the cell or animal is preferably an amount that does not induce any toxic effects which outweigh the advantages which accompany its administration.
• Actual dosage levels of active ingredients in the pharmaceutical compositions may vary so as to administer an amount of the active compound(s) that is effective to achieve the desired therapeutic response for a particular patient.
• the selected dose level may depend on the activity of the iminosugar, the route of
• the effective daily dose may be divided into multiple doses for purposes of administration, for example, two to four doses per day. It will be understood, however, that the specific dose level for any particular patient may depend on a variety of factors, including the body weight, general health, diet, time and route of administration and combination with other therapeutic agents and the severity of the condition or disease being treated.
• the adult human daily dosage may range from between about one microgram to about one gram, or from between about 10 mg and 100 mg, of the iminosugar per 10 kilogram body weight.
• a total daily dose may be from 0.1 mg/kg body weight to 100 mg/kg body weight or from 1 mg/kg body weight to 60 mg/kg body weight or from 2 mg/kg body weight to 50 mg/kg body weight or from 3 mg/kg body weight to 30 mg/kg body weight.
• the daily dose may be administered over one or more administering events over day. For example, in some embodiments, the daily dose may be distributed over two (BID) administering events per day, three administering events per day (TID) or four administering events (QID).
• a single administering event dose ranging from 1 mg/kg body weight to 10 mg/kg body weight may be administered BID or TID to a human making a total daily dose from 2 mg/kg body weight to 20 mg/kg body weight or from 3 mg/kg body weight to 30 mg/kg body weight.
• the amount of the iminosugar which should be administered to a cell or an animal may depend upon numerous factors well understood by one of skill in the art, such as the molecular weight of the iminosugar and the route of administration.
• compositions that are useful in the methods of the invention may be administered systemically in oral solid formulations, ophthalmic, suppository, aerosol, topical or other similar formulations.
• it may be in the physical form of a powder, tablet, capsule, lozenge, gel, solution, suspension, syrup, or the like.
• such pharmaceutical compositions may contain pharmaceutically-acceptable carriers and other ingredients known to enhance and facilitate drug administration.
• Other possible formulations, such as nanoparticles, liposomes, resealed erythrocytes, and immunologically based systems may also be used to administer the iminosugar.
• Such pharmaceutical compositions may be administered by a number of routes.
• parenteral used herein includes subcutaneous, intravenous, intraarterial, intrathecal, and injection and infusion techniques, without limitation.
• the pharmaceutical compositions may be administered orally, topically, parenterally, systemically, or by a pulmonary route.
• compositions may be administered in a single dose or in multiple doses which are administered at different times. Because the inhibitory effect of the composition upon a poxvirus may persist, the dosing regimen may be adjusted such that virus propagation is retarded while the host cell is minimally effected.
• an animal may be administered a dose of the composition of the invention once per week, whereby virus propagation is retarded for the entire week, while host cell functions are inhibited only for a short period once per week.
• the filtrate was concentrated in vacuo to get the crude product.
• the crude product was dissolved in dichloromethane and washed with water, and then brine, dried over sodium sulfate. The organic layer was concentrated in vacuo to get the crude product.
• the crude product was purified by column chromatography using 230-400 mesh silica gel. A solvent gradient of ethyl acetate in hexanes (10-45%) was used to elute the product from the column. All fractions containing the desired pure product were combined and concentrated in vacuo to give pure 6-propyloxy-l-hexanol (lot D-1029-048, 1.9 g, 25%>) Completion of the reaction was monitored by thin layer chromatography (TLC); (eluent: 60% ethyl acetate in hexanes).
• TLC thin layer chromatography
• the filtrate was concentrated in vacuo to get the crude product.
• the crude product was purified by column chromatography (230-400 mesh silica gel). A solvent gradient of methanol in dichloromethane (10-40%) was used to elute the product from the column. All fractions containing the desired product were combined, and concentrated in vacuo to give the pure product. (Lot: D- 1029-052 (840 mg). Completion of the reaction was monitored by thin layer chromatography (TLC); (eluent: 50% methanol in dichloromethane).
• the filtrate was concentrated in vacuo to get a crude product.
• the crude product was purified by column chromatography using 250-400 mesh silica gel (20 g). A solvent gradient of methanol in ethyl acetate (5- 25%) was used to elute the product from the column. All fractions containing the desired pure product were combined, and concentrated in vacuo to give an off white solid. The solid was triturated in ethyl acetate (20 mL), filtered and dried in high vacuum to give a white solid [lot: D-1027-158 (165.3 mg, 28.1%). Completion of the reaction was monitored by thin layer chromatography (TLC) using a thin layer silica gel plate; eluent: 50% methanol in
• Table 7 provides data for inhibition of infectivity of Vaccinia virus for NB-DNJ (UV-1), NN- DNJ (UV-2), N7-0-DNJ (UV-3), N9-DNJ (UV-4) and NAP -DNJ (UV-5).
• BSC-40 cells vervet monkey kidney epithelial cell line obtained from American Type Culture Collection (ATCC, Manassas, Virginia). Cells were cultured in lx modified Eagle medium (MEM, Gibco), supplemented with 5% fetal bovine serum, 2 mM L-glutamine, 100 U/ml penicillin, 100 ⁇ g/ml streptomycin in cell culture treated 24-well flat bottom plates at 37°C in a 5% C02 incubator for 24 hr or until 80% confluent prior to assay.
• MEM lx modified Eagle medium
• Viral supernatant were diluted from 10 " to 10 " and added to the cells and incubated at 37°C for 1 hour with shaking every 5-10 minutes.
• Viral infection medium were aspirated and replace with lmL pre-warmed 2% low-melt agarose mixed 1 : 1 with 2X MEM (5% fetal calf serum final concentration) and incubated at 37°C, 5% C0 2 for 2 days followed by plaque visualization by neutral red staining.
• This compound was previously tested in both in vitro (CC50 of 125 to >2,000uM) and in vivo (no weight loss or adverse effects observed in multiple mouse studies) and shown it possesses low toxicity.
• the compound was administered as a free drug dissolved in water.
• the UV-4 compound was given by the oral route (2x per day intragastric via oral gavage - IG) for a total number of 10 days after the start of the compound dosing. Study animals were infected intranasally with cowpox brighton with ⁇ 1 LD90 (1.00e6 pfu/mouse) 1 hour before the first UV-4 dose.
• Figure 5 shows survival data for mice that were infected with a lxLD90 dose of cowpox brighton and dosed 3x per day for 10 days with either water (control group) or UV-4 (treated group).
• Table 8 shows a percentage of surviving mice in a) the control group treated with water and b) the group treated with UV-4 on days indicated in the left column.
• Each of the control and treated groups included 10 mice.
• mice were given oral suspensions of UV-1, UV-4, UV-5, twice a day for seven days, in lOOul per mouse at 100 and 10 mg/kg (2mg and 0.2 mg/mouse, respectively) 8 hours apart for 7 days, and then monitored for weight loss and general health. After seven days of treatment, the mice did not show any significant signs of weight loss compared to the "vehicle only" control.
• the results of these experiments are in Figure 6.

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